Malaysia's HIV epidemic, historically driven by male people who inject drugs (PWIDs), has transitioned over the last two decades to a generalized epidemic with bridges between substance abuse and sexual transmission. During this period, females have accounted for a growing proportion of new HIV infections (from 1% in 1990 to 25% in 2011), which are overwhelmingly attributed to sexual transmission. Transgender women have also faced a growing HIV burden in the region, with recent evidence suggesting they are one of the highest at-risk subpopulations globally. Sex work and the frequent co-occurrence of substance abuse is a major risk factor for both females and transgender women, especially in Malaysia, which has become a major destination for sex tourism. Despite recommendations by international agencies (WHO, UNODC, UNAIDS) to implement innovative, combination approaches to HIV and substance abuse prevention, especially among women, uptake in Malaysia, and Southeast Asia generally, has been woefully inadequate. Novel approaches to addressing the complex syndemic of sex work and substance abuse among female and transgender sex workers (F/TGSWs) are in demand. The mentored projects proposed here address this need through the conduct of two formative research studies. The first will estimate the prevalence of HIV and STIs among F/TGSWs in Malaysia's Klang Valley, assess sexual and drug risk behaviors, and determine feasibility of behavioral and biomedical approaches to HIV and substance use prevention. The second study will build on the first by adapting behavioral and biomedical interventions to address co-occurring sexual and drug risk behaviors among F/TGSWs in the region. Findings from these projects will contribute to a greater understanding of HIV and substance abuse risk behaviors among the target population and establish the knowledge necessary to develop innovative approaches to addressing them. The candidate, Dr. Wickersham, is uniquely poised to perform this work because of his strong background in gender and women's studies, his research productivity in the area of public health, and his experience with research in the Malaysian context. Over the five years of this proposal, he will achieve his career goals and professional objectives to: 1) develop expertise in research methods necessary to design, perform, and adapt HIV risk reduction interventions and eventually conduct clinical trials relating to HIV and STI prevention among TGW and FSWs in Malaysia; 2) gain experience in intervention development, adaptation, testing, implementation, and dissemination that will address gender-specific barriers to HIV prevention and treatment services; and 3) develop an independent career path in patient-oriented research focused on the interface between HIV, women's health, gender, and substance abuse and prevention. To achieve these goals, Dr. Wickersham has assembled a team of outstanding leaders in the fields of HIV, substance abuse, epidemiology, and behavioral and biomedical intervention science. Under their guidance, he will complete relevant coursework, attend seminars, and conduct research to apply the skills necessary to become an independent investigator in HIV and substance abuse prevention among female and transgender women sex workers in the Malaysian context.